<i>ARF1</i>-related disorder: phenotypic and molecular spectrum.

Abstract

<i>ARF1</i> was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of <i>ARF1</i>-related neurodevelopmental disorder. We collected detailed phenotypes of an international cohort of individuals (n=17) with <i>ARF1</i> variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in <i>ARF1</i> were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. We confirm the role of <i>ARF1</i> in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.